A strategy for catalyst-controlled regioselectivity in aldehyde-alkyne reductive couplings has been developed. This strategy is the first where either regiochemical outcome may be selected for a broad range of couplings, without relying on substrate biases or directing effects. The complementary use of small cyclopropenylidene carbene ligands or highly hindered N-heterocyclic carbene ligands allows the regiochemical reversal with unbiased internal alkynes, aromatic internal alkynes, conjugated enynes, or terminal alkynes.The reductive coupling of aldehydes and alkynes has been widely studied as an entry to stereodefined allylic alcohols. 1 While broad scope has been demonstrated for several variants, the control of regiochemistry is consistently a major hurdle. 2 Indeed, the challenge of controlling regiochemistry plagues nearly every class of alkyne addition reactions. In most classes of addition processes, alkynes that possess either a strong electronic or steric bias often participate with good to excellent regiocontrol, but only a single regiochemical outcome is typically available. Alternatively, alkynes that lack a strong electronic or steric bias generally participate in addition processes with poor regioselectivity. These characteristics generally hold true for aldehyde-alkyne reductive coupling processes. Aromatic alkynes, terminal alkynes, silyl alkynes, ynamides, and conjugated diynes and enynes are among the biased substrate classes that participate in highly regioselective reductive couplings with aldehydes, with a single regiochemical outcome typically being possible. 3 Additionally, remote directing functionality such as alkenes and alcohols have proven to be effective in Ni-catalyzed and Tipromoted variants. 2,4 Despite these impressive advances with biased alkynes and directed processes, we envisioned that a strategy for regiochemical control that overrides inherent substrate biases and that does not require installation of a directing functional group would be the ideal solution to regiocontrol in this group of reactions. Previous results from our lab illustrated that regioselectivities may be moderately impacted by ligand structure, but the effects were too small to be broadly useful. 5 A recent computational study described the minimal impact that jmontg@umich.edu. Supporting Information Available: Full experimental details and copies of NMR spectral data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. ligand structure has on regioselectivity in aldehyde-alkyne reductive couplings with Ni(0)-phosphine catalysts and organoborane reducing agents, 6 thus highlighting the complexity of designing a ligand-controlled regioselective process. Herein, we describe that carefully selected carbene ligands complexed with nickel provide a general solution to regiocontrol in silane-mediated aldehyde-alkyne reductive couplings with a broad range of alkynes. NIH Public AccessOur studies began with an evaluation of ligand effects in reductive couplings of h...

CONSPECTUS The control of regiochemistry is a considerable challenge in the development of a wide array of catalytic processes. Simple π-components such as alkenes, alkynes, 1,3-dienes, and allenes are among the many classes of substrates that present complexities in regioselective catalysis. Considering an internal alkyne as a representative example, when steric and electronic differences between the two substituents are minimal, differentiating among the two termini of the alkyne presents a great challenge. In cases where the differences between the alkyne substituents are substantial, overcoming those biases to access the regioisomer opposite that favored by substrate biases often presents an even greater challenge. Nickel-catalyzed reductive couplings of unsymmetrical π-components make up a group of reactions where control of regiochemistry presents a challenging but important objective. In the course of our studies of aldehyde-alkyne reductive couplings, complementary solutions to challenges in regiocontrol have been developed. Through careful selection of the ligand and reductant, as well as the more subtle reaction variables such as temperature and concentration, effective protocols have been established that allow highly selective access to either regiosiomer of the the allylic alcohol products using a wide range of unsymmetrical alkynes. Computational studies and an evaluation of reaction kinetics have provided an understanding of the origin of the regioselectivity control. Throughout the various procedures described, the development of ligand-substrate interactions play a key role, and the overall kinetic descriptions were found to differ between protocols. Rational alteration of the rate-determining step plays a key role in the regiochemistry reversal strategy, and in one instance, the two possible regioisomeric outcomes in a single reaction were found to operate by different kinetic descriptions. With this mechanistic information in hand, the empirical factors that influence regiochemistry can be readily understood, and more importantly, the insights suggest simple and predictable experimental variables to achieving a desired reaction outcome. These studies thus present a detailed picture of the influences that control regioselectivity in a specific catalytic reaction, but they also delineate strategies for regiocontrol that may extend to numerous classes of reactions. The work provides an illustration of how insights into the kinetics and mechanism of a catalytic process can rationalize subtle empirical findings and suggest simple and rational modifications in procedure to access a desirable reaction outcome. Furthermore, these studies present an illustration of how important challenges in organic synthesis can be met by novel reactivity afforded by base metal catalysis. The use of nickel catalysis in this instance not only provides an inexpensive and sustainable method for catalysis, but also enables unique reactivity patterns not accessible to other metals.

Allylic alcohols are integral subunits of a variety of biologically interesting natural products as well as key building blocks for a number of important synthetic transformations. Among the numerous strategies for the preparation of allylic alcohols, the reductive coupling of aldehydes and alkynes in either an inter-or intramolecular sense arguably provides the most direct access to this important substructure from simple precursors. 1,2 Whereas several asymmetric approaches to the reductive coupling of aldehydes and alkynes have been reported, 3 our recent studies involving the use of achiral N-heterocyclic carbene complexes of nickel illustrated several important features including broad scope with both internal and terminal alkynes, direct incorporation of a silyl protecting group, and the ability to tune alkyne regioselection in macrocyclizations based on ligand sterics. 4 In order to capitalize upon these advantages, we have now examined the asymmetric coupling of aldehydes and alkynes using chiral N-heterocyclic carbene complexes.Pioneering studies from Grubbs illustrated that N-heterocyclic carbenes derived from C-2 symmetric diamines and mono-ortho-substituted aryl halides were excellent participants in asymmetric ring-closing metathesis reactions. 5 Members of this structural class of Nheterocyclic carbenes appeared to be promising candidates for asymmetric nickel-catalyzed reductive couplings. We thus examined the reductive coupling of benzaldehyde and 1-phenylpropyne under a variety of conditions to provide a lead ligand structure for further optimization. The known N-heterocyclic carbene ligands, generated in situ from 1a and 1b in THF with KO-t-Bu, allowed the production of the desired protected allylic alcohol 2a in modest yield and poor enantioselectivity (Table 1). New ligands 1c and 1d, which incorporate an ortho-phenyl or ortho-cyclohexyl substituent, were then prepared from the commercially available aryl bromides. A reaction involving ligand 1c afforded product 2a with slightly improved enantioselectivity, whereas a reaction with ligand 1d proceeded with significantly improved enantioselectivity, affording compound 2a in 76% ee in 60% yield. Despite the encouraging enantioselectivity with ligand 1d, examination of additional starting material combinations illustrated that yields were often poor to modest. Given the requirement of steric hindrance to stabilize free N-heterocyclic carbenes (by preventing dimerization), we next considered ortho,ortho-disubstituted carbene ligands. Ligand 1e was thus prepared, which did indeed allow improved chemical yields but with low enantioselectivities. Recognizing that ortho,ortho-disubstitution was optimal from the standpoint of chemical yield, whereas steric differentiation of the two ortho substituents was optimal from the standpoint of enantioselectivity, we next prepared ligand 1f. Under the same conditions described for the above experiments, chemical yields in couplings of benzaldehyde and 1-phenylpropyne jmontg@umich.edu. Supporting Information Ava...

An exceptionally hindered class of enantiopure NHC ligands has been developed. While racemic forms had previously been utilized, a scalable and practical route to the enantiopure form of this ligand class is described utilizing a two-directional Buchwald-Hartwig amination in a highly sterically demanding environment. Using this newly accessible ligand class, nickel-catalyzed enantioselective reductive coupling reactions of aldehydes and alkynes has been developed. These studies illustrate that the newly available NHC ligands are well suited for simultaneous control of regio- and enantioselectivity, even in cases with internal alkynes possessing only very subtle steric differences in two aliphatic substituents. The steric demand of the new ligand class enables a complementary regiochemical outcome compared with previously described enantioselective processes. Using this method, a number of allylic alcohol derivatives were efficiently obtained with high regioselectivity (up to >95:5) and high enantioselectivity (up to 94% ee). The reaction conditions can also be extended to the reaction of aldehydes and allenes, providing silyl-protected allylic alcohol derivatives possessing a terminal methylene substituent. Computational studies have explained the origin of the exceptional steric demand of this ligand class, the basis for enantioselectivity, and the cooperative relationship of the aldehyde, alkyne, and ligand in influencing enantioselectivity.

Alcohols P 0110New N-Heterocyclic Carbene Ligand and Its Application in Asymmetric Nickel--Catalyzed Aldehyde/Alkyne Reductive Couplings. -Various functional groups are tolerated in the procedure. Generally, the trialkylsilyl group is regioselectively installed at the newly formed hydroxyl group. In the case of substrate (IId), the regioselectivity in the coupling with (VI) is reversed with ligand (Ib). The methodology is also applied to the asymmetric macrocyclization of ynal (IX). In this case, the regioselection is reversed in comparison to intermolecular examples. -(CHAULAGAIN, M. R.; SORMUNEN, G. J.; MONTGOMERY*, J.; J. Am. Chem. Soc. 129 (2007) 31, 9568-9569; Dep. Chem., Univ. Mich., Ann Arbor, MI 48109, USA; Eng.) -Bartels 50-059